Parkinson Disease

Parkinson Disease Treatment: Drugs

 

Drug Treatments

Medications for Parkinson Disease fall into three categories. The first category includes drugs that work directly or indirectly to increase the level of dopamine in the brain.  The most common drugs for Parkinson Disease are dopamine precursors – substances such as levodopa that cross the blood-brain barrier and are then changed into dopamine. Other drugs mimic dopamine or prevent or slow its breakdown.

The second category of Parkinson Disease drugs affects other neurotransmitters in the body in order to ease some of the symptoms of the disease. For example, anticholinergic drugs interfere with production or uptake of the neurotransmitter acetylcholine. These drugs help to reduce tremors and muscle stiffness, which can result from having more acetylcholine than dopamine.

The third category of drugs prescribed for Parkinson Disease includes medications that help control the non-motor symptoms of the disease, that is, the symptoms that don't affect movement. For example, people with Parkinson Disease-related depression may be prescribed antidepressants.

• Levodopa.  The cornerstone of therapy for Parkinson Disease is the drug levodopa (also called L-dopa). Levodopa (from the full name L-3,4-dihydroxyphenylalanine) is a simple chemical found naturally in plants and animals. Levodopa is the generic name used for this chemical when it is formulated for drug use in patients. Nerve cells can use levodopa to make dopamine and replenish the brain's dwindling supply. People cannot simply take dopamine pills because dopamine does not easily pass through the blood-brain barrier, a lining of cells inside blood vessels that regulates the transport of oxygen, glucose, and other substances into the brain.  Usually, patients are given levodopa combined with another substance called carbidopa. When added to levodopa, carbidopa delays the conversion of levodopa into dopamine until it reaches the brain, preventing or diminishing some of the side effects that often accompany levodopa therapy. Carbidopa also reduces the amount of levodopa needed.

  Levodopa is very successful at reducing the tremors and other symptoms of Parkinson Disease during the early stages of the disease.  It allows the majority of people with Parkinson Disease to extend the period of time in which they can lead relatively normal, productive lives.

  Although levodopa helps most people with Parkinson Disease, not all symptoms respond equally to the drug. Levodopa usually helps most with bradykinesia and rigidity. Problems with balance and other non-motor symptoms may not be alleviated at all.

  People who have taken other medications before starting levodopa therapy may have to cut back or eliminate these drugs in order to feel the full benefit of levodopa. People often see dramatic improvement in their symptoms after starting levodopa therapy.  However, they may need to increase the dose gradually for maximum benefit. A high-protein diet can interfere with the absorption of levodopa, so some physicians recommend that patients taking the drug restrict their protein consumption during the early parts of the day or avoid taking their medications with protein-rich meals.

  Levodopa is often so effective that some people may temporarily forget they have Parkinson Disease during the early stages of the disease. But levodopa is not a cure. Although it can reduce the symptoms of Parkinson Disease, it does not replace lost nerve cells and it does not stop the progression of the disease.

  Levodopa can have a variety of side effects. The most common initial side effects include nausea, vomiting, low blood pressure, and restlessness. The drug also can cause drowsiness or sudden sleep onset, which can make driving and other activities dangerous.  Long-term use of levodopa sometimes causes hallucinations and psychosis.  The nausea and vomiting caused by levodopa are greatly reduced by combining levodopa and carbidopa, which enhances the effectiveness of a lower dose.

  Dyskinesias, or involuntary movements such as twitching, twisting, and writhing, commonly develop in people who take large doses of levodopa over an extended period. These movements may be either mild or severe and either very rapid or very slow. The dose of levodopa is often reduced in order to lessen these drug-induced movements.  However, the Parkinson Disease symptoms often reappear even with lower doses of medication. Doctors and patients must work together closely to find a tolerable balance between the drug's benefits and side effects. If dyskinesias are severe, surgical treatment may be considered. Because dyskinesias tend to occur with long-term use of levodopa, doctors often start younger Parkinson Disease patients on other dopamine-increasing drugs and switch to levodopa only when those drugs become ineffective.

  Other troubling and distressing problems may occur with long-term levodopa use. Patients may begin to notice more pronounced symptoms before their first dose of medication in the morning, and they may develop muscle spasms or other problems when each dose begins to wear off. The period of effectiveness after each dose may begin to shorten, called the wearing-off effect. Another potential problem is referred to as the on-off effect — sudden, unpredictable changes in movement, from normal to parkinsonian movement and back again. These effects probably indicate that the patient's response to the drug is changing or that the disease is progressing.

  One approach to alleviating these side effects is to take levodopa more often and in smaller amounts.  People with Parkinson Disease should never stop taking levodopa without their physician's knowledge or consent because rapidly withdrawing the drug can have potentially serious side effects, such as immobility or difficulty breathing.

Fortunately, physicians have other treatment choices for some symptoms and stages of Parkinson Disease. These therapies include the following:

• Dopamine agonists.  These drugs, which include bromocriptine, pergolide, apomorphine, pramipexole, and ropinirole, mimic the role of dopamine in the brain. They can be given alone or in conjunction with levodopa. They may be used in the early stages of the disease, or later on in order to lengthen the duration of response to levodopa in patients who experience wearing off or on-off effects.  They are generally less effective than levodopa in controlling rigidity and bradykinesia.  Many of the potential side effects are similar to those associated with the use of levodopa, including drowsiness, sudden sleep onset, hallucinations, confusion, dyskinesias, edema (swelling due to excess fluid in body tissues), nightmares, and vomiting.  In rare cases, they can cause compulsive behavior, such as an uncontrollable desire to gamble, hypersexuality, or compulsive shopping.  Bromocriptine and pergolide sometimes also cause fibrosis, or a buildup of fibrous tissue, in the heart valves or the chest cavity.  Fibrosis usually goes away once the drugs are stopped.

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• MAO-B inhibitors. These drugs inhibit the enzyme monoamine oxidase B, or MAO-B, which breaks down dopamine in the brain.  MAO-B inhibitors cause dopamine to accumulate in surviving nerve cells and reduce the symptoms of Parkinson Disease.  Selegiline, also called deprenyl, is an MAO-B inhibitor that is commonly used to treat Parkinson Disease. Studies supported by the NINDS have shown that selegiline can delay the need for levodopa therapy by up to a year or more. When selegiline is given with levodopa, it appears to enhance and prolong the response to levodopa and thus may reduce wearing-off fluctuations.  Selegiline is usually well-tolerated, although side effects may include nausea, orthostatic hypotension, or insomnia.  It should not be taken with the antidepressant fluoxetine or the sedative mepiridine, because combining seligiline with these drugs can be harmful.  An NINDS-sponsored study of seligiline in the late 1980s suggested that it might help to slow the loss of nerve cells in Parkinson Disease.  However, follow-up studies cast doubt on this finding. Another MAO-B inhibitor, rasagiline, was approved by the FDA in May 2006 for use in treating Parkinson Disease.
   

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• COMT inhibitors.  COMT stands for catechol-O-methyltransferase, another enzyme that helps to break down dopamine.  Two COMT inhibitors are approved to treat Parkinson Disease in the United States:  entacapone and tolcapone.  These drugs prolong the effects of levodopa by preventing the breakdown of dopamine. COMT inhibitors can decrease the duration of "off" periods, and they usually make it possible to reduce the person's dose of levodopa.  The most common side effect is diarrhea.  The drugs may also cause nausea, sleep disturbances, dizziness, urine discoloration, abdominal pain, low blood pressure, or hallucinations.  In a few rare cases, tolcapone has caused severe liver disease.  Because of this, patients taking tolcapone need regular monitoring of their liver function.

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• Amantadine. An antiviral drug, amantadine, can help reduce symptoms of Parkinson Disease and levodopa-induced dyskinesia.  It is often used alone in the early stages of the disease.  It also may be used with an anticholinergic drug or levodopa.  After several months, amantadine's effectiveness wears off in up to half of the patients taking it. Amantadine's side effects may include insomnia, mottled skin, edema, agitation, or hallucinations. Researchers are not certain how amantadine works in Parkinson Disease, but it may increase the effects of dopamine.

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• Anticholinergics. These drugs, which include trihexyphenidyl, benztropine, and ethopropazine, decrease the activity of the neurotransmitter acetylcholine and help to reduce tremors and muscle rigidity.  Only about half the patients who receive anticholinergics are helped by it, usually for a brief period and with only a 30 percent improvement.  Side effects may include dry mouth, constipation, urinary retention, hallucinations, memory loss, blurred vision, and confusion.

When recommending a course of treatment, a doctor will assess how much the symptoms disrupt the patient's life and then tailor therapy to the person's particular condition. Since no two patients will react the same way to a given drug, it may take time and patience to get the dose just right. Even then, symptoms may not be completely alleviated.

Medications to Treat the Motor Symptoms of Parkinson's Disease

Drugs that increase brain levels of dopamine Levodopa Drugs that mimic dopamine (dopamine agonists) Apomorphine Bromocriptine Pergolide Pramipexole Ropinirole   Drugs that inhibit dopamine breakdown (MAO-B inhibitors) Selegiline (deprenyl) Drugs that inhibit dopamine breakdown (COMT inhibitors) Entacapone Tolcapone Drugs that decrease the action of acetylcholine anticholinergics) Trihexyphenidyl Benztropine Ethopropazine Drugs with an unknown mechanism of action for Parkinson Disease Amantadine

Medications for Non-Motor Symptoms.   Doctors may prescribe a variety of medications to treat the non-motor symptoms of Parkinson Disease, such as depression and anxiety.  For example, depression can be treated with standard anti-depressant drugs such as amytriptyline or fluoxetine (however, as stated earlier, fluoxetine should not be combined with MAO-B inhibitors).  Anxiety can sometimes be treated with drugs called benzodiazepines.  Orthostatic hypotension may be helped by increasing salt intake, reducing antihypertension drugs, or prescribing medications such as fludrocortisone. 

Hallucinations, delusions, and other psychotic symptoms are often caused by the drugs prescribed for Parkinson Disease.  Therefore reducing or stopping Parkinson Disease medications may alleviate psychosis.  If such measures are not effective, doctors sometimes prescribe drugs called atypical antipsychotics, which include clozapine and quetiapine.  Clozapine also may help to control dyskinesias.  However, clozapine also can cause a serious blood disorder called agranulocytosis, so people who take it must have their blood monitored frequently.

National Institute of Neurological Disorders and Stroke (NINDS)
National Institutes of Health
Brain Resources and Information Network

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